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Endocrine Abstracts (2016) 41 OC10.2 | DOI: 10.1530/endoabs.41.OC10.2

ECE2016 Oral Communications Reproduction & Endocrine Disruption (5 abstracts)

Human luteinizing hormone (hLH) and chorionic gonadotropin (hCG) display biased agonism at the LH/CG receptor

Laura Riccetti 1 , Mohammed Akli Ayoub 2, , Daniele Klett 2 , Romain Yvinec 2 , Nathalie Gallay 2 , Yves Combarnous 2 , Livio Casarini 1, , Manuela Simoni 1, & Eric Reiter 2

1Unit of Endocrinology, Department of Biomedicine, Metabolism and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy; 2Biologie et Bioinformatique des Systèmes de Signalisation (BIOS) group, INRA, UMR85, Unitè Physiologie de la Reproduction et des Comportements; CNRS, UMR7247, F-37380, Nouzilly, France; 3LE STADIUM Loire Valley Institute for Advanced Studies, F-45000 Orlèans, France; 4Center for Genome Research, University of Modena and Reggio Emilia, Modena, Italy.

Human luteinizing hormone (LH) and human choriogonadotropin (hCG) were considered biologically equivalent for decades due to structural similarities and binding to the same receptor (LHCGR). However, LHCGR triggers differential, LH- and hCG-specific, cAMP production, steroidogenesis, ERK and AKT activation and gene expression in granulosa cells. Besides the Gs/cAMP/PKA pathway, hCG and LH bioactivity on β-arrestin- and Gq/PLC-dependent pathways are yet to be determined. We compared the abilities of recombinant hLH and hCG to elicit cAMP and inositol phosphate production, β-arrestin 2 activation and recruitment, as well as steroids production in two cell models: i) human embryonic kidney 293 (HEK293) cells transiently expressing LHCGR; ii) mouse Leydig tumour cells (mLTC-1), endogenously expressing the murine LH receptor. Bioluminescence/fluorescence resonance energy transfer (BRET/FRET) technologies were used, allowing quantitative analysis of hCG/hLH activities in real-time in living cells treated by increasing doses of gonadotropins (1 pM-1 μM). Both hormones trigger identical maximal cAMP response, with the EC50 of hCG 30 times lower than that of hLH (12.91±1.48 pM versus 378.6±1.2 pM, respectively) (Mann-Whitney’s U-test; P<0.05; n=4). hLH clearly led to weaker maximal response of progesterone production than hCG (hCG=94.36±3.1%; LH=41.46±4.1%; t-test; P<0.05; n=3), exhibiting partial agonism for steroids synthesis. IP1 production and β-arrestin responses confirmed the biased actions of the two hormones. EC50 values measured for IP1 production were higher compared to EC50s obtained for cAMP, indicating that higher receptor occupancy must be reached to recruit Gαq than Gαs. Moreover, we found that hLH led to partial maximal β-arrestin 2 recruitment, with 5-fold lower potency compared to hCG (hLH=0.14±0.008 versus hCG=0.2±0.008; Mann-Whitney’s U-test; P<0.05; n=4). These results challenge the traditional view that hLH and hCG are biologically equivalent, since they trigger clearly different intracellular responses and suggest that these pleiotropic gonadotropins could act as natural biased agonists in vivo, opening novel pathophysiological scenarios.

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